The three main mammalian tachykinins, substance P (SP), neurokinin A(NKA) and neurokinin B (NKB) belong to the family of neuropeptides sharing the common COOH-terminal pentapeptide sequence of Phe-X-Gly-Leu-Met-NH2. As neurotransmitters, these peptides exert their biological activity via three distinct neurokinin (NK) receptors termed as NK-1, NK-2 and NK-3. SP binds preferentially to the NK-1 receptor, NKA to the NK-2 and NKB to the NK-3 receptor.
The NK-3 receptor is characterized by a predominant expression in CNS and its involvement in the modulation of the central monoaminergic system has been shown. These properties make the NK-3 receptor a potential target for central nervous system disorders such as anxiety, depression, bipolar disorders, Parkinson's disease, schizophrenia and pain (Neurosci. Letters, 2000, 283, 185-188; Exp. Opin. Ther. Patents 2000, 10, 939-960; Neuroscience, 1996, 74, 403-414; Neuropeptides, 1998, 32, 481-488).
Neurokinin 3 receptors are expressed in the brain and strategically located along with NKB, i.e. its natural substrate, in noradrenergic and dopaminergic pathways. Indeed, CNS administration of senktide, a peptide agonist of NK-3 receptors, increases noradrenaline and dopamine in brain areas such as the prefrontal cortex. NK-3 receptors are less abundant in serotonergic pathways, nevertheless, intracerebroventricular administration of senktide elicits behavioural manifestations of serotonergic stimulation, such as forepaw treading, that were blocked by serotonin depletion (Stoessl et al., 1989, Neurosci. Letters, 1987, 80(3), 321-6).
Thus, activation of NK-3 receptors stimulates noradrenergic, dopaminergic and serotonergic systems, i.e., those that are critically involved in the anti-depressant and anxiolytic effects of SSRI's (serotonin re-uptake inhibitors) and SNRI's (serotonin noradrenaline re-uptake inhibitors (Millan et al., Psychopharmacoogy 14 (2000), 114-138). Indeed, preliminary mice studies suggest that intraperitoneal administration of the NK-3 agonist aminosenktide exhibits anti-depressant-like effects in the forced swimming test (Panocka et al, Peptides, 2001, 22(7), 1037-42), and that intracerebroventricular administration of senktide exhibits anxiolytic-like effects in the elevated plus maze (Ribeiro and De Lima, Neurosci Letters, 1998, 258(3), 155-8).
In addition, because cognitive impairment may be an important element of these diseases (Knapp et al., Br J Psychiatry, 2002, 18, 19-23), it is of great interest that senktide, after its local administration in the area of cholinergic cell bodies (septal area) stimulates acetylcholine in the hippocampus. Indeed, senktide ameliorates the scopolamine-induced impairment in a cognition test (Kameyama et al., Methods Find Exp Clin Pharmacol, 1998, 20(7), 555-60).
In conclusion, based on biochemical and behavioral data, activation of NK-3 receptors is expected to lead to anti-depressant and anxiolytic-like effects, and in addition, to ameliorate possible cognitive deficits for the treatment of anxiety, depression, bipolar disorders, Parkinson's disease, schizophrenia and pain.